The Notch gene was first described in 1917 when a strain of the fruit fly Drosophila melanogaster was found to have notched wing blades (Morgan, Am Nat 51:513 (1917)). The gene was cloned almost seventy years later and was determined to be a cell surface receptor playing a key role in the development of many different cell types and tissues in Drosophila (Wharton et al., Cell 43:567 (1985)). The Notch signaling pathway was soon found to be a signaling mechanism mediated by cell-cell contact and has been evolutionarily conserved from Drosophila to human. Notch receptors have been found to be involved in many cellular processes, such as differentiation, cell fate decisions, maintenance of stem cells, cell motility, proliferation, and apoptosis in various cell types during development and tissue homeostasis (See review Artavanis-Tsakonas, et al., Science 268:225 (1995)).
Mammals possess four Notch receptor proteins (designated Notch1 to Notch4) and five corresponding ligands (designated Delta Like-1 (DLL-1), Delta Like-3 (DLL-3), Delta Like-4 (DLL-4), Jagged-1 and Jagged-2). The mammalian Notch receptor genes encode ˜300 kD proteins that are cleaved during their transport to the cell surface and exist as heterodimers. The extracellular portion of the Notch receptor has thirty-four epidermal growth factor (EGF)-like repeats and three cysteine-rich Notch/LIN12 repeats. The association of two cleaved subunits is mediated by sequences lying immediately N-terminal and C-terminal of the cleavage site, and these two subunits constitute the Notch heterodimerization (HD) domains (Wharton, et al., Cell 43:567 (1985); Kidd, et al., Mol Cell Biol 6:3431 (1986); Kopczynski, et al., Genes Dev 2:1723 (1988); Yochem, et al., Nature 335:547 (1988)).
At present, it is still not clear how Notch signaling is regulated by different receptors or how the five ligands differ in their signaling or regulation. The differences in signaling and/or regulation may be controlled by their expression patterns in different tissues or by different environmental cues. It has been documented that Notch ligand proteins, including Jagged/Serrate and Delta/Delta-like, specifically bind to the EGF repeat region and induce receptor-mediated Notch signaling (reviewed by Bray, Nature Rev Mol Cell Biol. 7:678 (2006), and by Kadesch, Exp Cell Res. 260:1 (2000)). Among the EGF repeats, the 10th to 12th repeats are required for ligand binding to the Notch receptor, and the other EGF repeats may enhance receptor-ligand interaction (Xu, et al., J Biol Chem. 280:30158 (2005); Shimizu, et al., Biochem Biophys Res Comm. 276:385 (2000)). Although the LIN12 repeats and the dimerization domain are not directly involved in ligand binding, they play important roles in maintaining the heterodimeric protein complex, preventing ligand-independent protease cleavage and receptor activation (Sanche-Irizarry, et al., Mol Cell Biol. 24:9265 (2004); Vardar et al., Biochem. 42:7061 (2003)).
Normal stem cells from many tissues including intestinal and neuronal stem cells depend on Notch signaling for self-renewal and fate determination (Fre, et al., Nature, 435: 964 (2005); van Es, et al., Nature, 435: 959 (2005); Androutsellis-Theotokis, et al., Nature, 442: 823 (2006)). Therefore, the Notch3 agonistic antibody could have application in degenerative diseases. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia. CADASIL has been found to be associated with a mutant gene localized to chromosome 19 (Joutel, et al., Nature 383:707 (1996)). Joutel et al. identified mutations in CADASIL patients that cause serious disruption of the Notch 3 gene, indicating that Notch3 could be the defective protein in CADASIL patients. Unfortunately, this highly incapacitating and often lethal disease has remained largely undiagnosed or misdiagnosed as multiple sclerosis and Alzheimer's disease. Current studies would tend to demonstrate that it is a condition that is much more widespread than first thought.
An additional example of a Notch 3 related disease is familial hemiplegic migraine (FHM), the dominant autosomal form of migraine with aura, located in the same region of chromosome 19 as the Notch3 gene. It should be noted that more than 30% of patients suffering from CADASIL also suffer from migraine with aura. However, the latter is observed in only about 5% of the population and this observation led to the discovery of Notch3 gene involvement in the mechanism of this condition. Similarly, familial paroxytic ataxia has been linked to a gene located in the same region of chromosome 19 and Notch3 has been implicated in this condition. Other conditions and diseases that have been linked to Notch3 include Alagille syndrome (Flynn, et al., J Pathol 204:55 (2004)).
Ongoing research studies are currently being pursued to identify other diseases and conditions linked to Notch3 expression and/or signaling deficiencies. In view of the large number of human diseases associated with the Notch 3 signaling pathway, it is important that new ways of preventing and treating these diseases be identified. The current invention provides novel anti-Notch 3 agonist antibodies useful for this unmet medical need.